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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.


Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.

WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 9)

CD52-directed antibody therapy

Alemtuzumab is a humanized monoclonal antibody which targets CD52, an antigen widely expressed on bone marrow LPC in WM patients, as well as on mast cells which are increased in the BM of patients with WM and provide growth and survival signals to WM LPC through several TNF family ligands (CD40L, APRIL, BLYS).166 As part of a WMCTG effort167, 28 subjects with the REAL/WHO clinicopathological diagnosis of LPL, including 27 patients with IgM (WM) and one with IgA monoclonal gammopathy were enrolled in this prospective, multicenter study.  Five patients were untreated and 23 were previously treated, all of whom had previously received rituximab. Patients received 3 daily test doses of alemtuzumab (3, 10, and 30 mg IV) followed by 30 mg alemtuzumab IV three times a week  for up to 12 weeks. All patients received acyclovir and bactrim or equivalent prophylaxis for the duration of therapy plus 8 week following the last infusion of alemtuzumab. Among 25 patients evaluable for response, the overall response rate was 76%, which included 8 (32%) major responders, and 11 (44%) minor responders. Hematological toxicities were common among previously treated (but not untreated) patients and included grade 3/4 neutropenia 39%; thrombocytopenia 18%; anemia 7%. Grade 3/4 non-hematological toxicity for all patients included dermatitis 11%; fatigue 7%; and infection 7%. CMV reactivation and infection was commonly seen among previously treated patients and may have been etiological for one death on study. With a median follow-up of 8.5+ months, 11/19 responding patients remain free of progression. High rates of response with the use of alemtuzumab as salvage therapy have also been reported by Owen et al168 in a small series of heavily pretreated WM patients (with a median prior therapies of 4) who received up to 12 weeks of therapy (at 30 mg IV TIW) following initial dose escalation. Among the 7 patients receiving alemtuzumab, 5 patients achieved a partial response and 1 patient a complete response. Infectious complications were common, with CMV reactivation occurring in 3 patients requiring ganciclovir therapy, and hospitalization for 3 patients for bacterial infections. Opportunistic infection occurred in two patients, and was responsible for their deaths.

Thalidomide and Lenalidomide

Thalidomide as a single agent, and in combination with dexamethasone and clarithromycin, has also been examined in patients with WM, in view of the success of these regimens in patients with advanced multiple myeloma. Dimopoulos et al169 demonstrated a major response in five of 20 (25%) previously untreated and treated patients who received single-agent thalidomide. Dose escalation from the thalidomide start dose of 200 mg daily was hindered by development of side effects, including the development of peripheral neuropathy in five patients obligating discontinuation or dose reduction. Low doses of thalidomide (50 mg orally daily) in combination with dexamethasone (40 mg orally once a week) and clarithromycin (250 mg orally twice a day) have also been examined,with 10 of 12 (83%) previously treated patients demonstrating at least a major response.170 However, in a follow-up study by Dimopoulos et al171 using a higher thalidomide dose (200 mg orally daily) along with dexamathasone (40 g orally once a week) and clarithromycin (500 mg orally twice a day), only two of ten (20%) previously treated patients responded. In a previous study, the immunomodulators thalidomide and its analogue lenalidomide significantly augmented rituximab mediated antibody dependent cell mediated cytotoxicity (ADCC) against lymphoplasmacytic cells.172 Moreover, an expansion of natural killer cells has been observed with thalidomide, which in previous studies have been shown to be associated with rituximab response.173,174 In view of these data, the WMCTG conducted 2 phase II clinical trials in symptomatic patients with WM combining thalidomide or lenalidomide with rituximab.175,176 Intended therapy for those patients who treated on the thalidomide plus rituximab study consisted of thalidomide administered at 200 mg daily for 2 weeks, followed by 400 mg daily thereafter for one year. Patients received four weekly infusions of rituximab at 375 mg/m2 beginning one week after initiation of thalidomide, followed by four additional weekly infusions of rituximab at 375 mg/m2 beginning at week 13. The overall and major response rate (i.e. >50 decrease in IgM) was 72% and 64%, respectively. Median serum IgM levels decreased from 3,670 to 1,590 mg/dL, while the median hematocrit rose from 33.0 to 37.6% at best response. The median time to progression for responders was 38 months in thise series. Dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients. Among 11 patients experiencing grade >2 neuroparesthesias, 10 demonstrated resolution to grade 1 or less at a median of 6.7 months. Given the high incidence of treatment related neuropathy, the investigators recommended that lower doses of thalidomide (i.e. < 200 mg/day) should be considered in this patient population.

In a phase II study of lenalidomide and rituximab in WM176, patients were initiated on lenalidomide at 25 mg daily on a syncopated schedule wherein therapy was administered for 3 weeks, followed by a one week pause for an intended duration of 48 weeks. Patients received one week of therapy with lenalidomide, after which rituximab (375 mg/m2) was administered weekly on weeks 2-5, then 13-16. The overall and a major response rates in this study were 50% and 25%, respectively, and a median TTP for responders was 18.9 months. In two patients with bulky disease, significant reduction in extramedullary disease was observed. However, an acute decrease in hematocrit were observed during first 2 weeks of lenalidomide therapy in 13/16 (81%) patients with a median absolute decrease inhematocrit of 4.8%, resulting in anemia related complications and hospitalizations in 4 patients. Despite dose reduction, most patients in this study continued to demonstrate aggravated anemia with lenalidomide. There was no evidence of hemolysis or more general myelosuppression with lenalidomide in this study. Therefore, the mechanism for lenalidomide related anemia in WM patients remains to be determined, and the use of this agent among WM patients should be avoided.

HIGH-DOSE THERAPY AND STEM CELL TRANSPLANTATION

The use of stem cell transplantion (SCT) therapy has also been explored in patients WM. Desikan et al177 reported their initial experience of high-dose chemotherapy and autologous stem cell transplant, which has more recently been updated by Munshi et al.178 Their studies involved eight previously treated WM patients between the ages of 45 and 69 years, who received either melphalan at 200mg/m2 (n = 7) or melphalan at 140mg/m2 along with total body irradiation. Stem cells were successfully collected in all eight patients, although a second collection procedure was required for two patients who had extensive previous nucleoside analogue exposure. There were no transplant related mortalities and toxicities were manageable. All eight patients responded, with 7 of 8 patients achieving a major response, and one patient achieving a complete response with durations of response raging from 5+ to 77+ months. Dreger et al179 investigated the use of the DEXA-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) regimen followed by myeloablative therapy with cyclophosphamide, and total body irradiation and autologous stem cell transplantation in seven WM patients, which included four untreated patients. Serum IgM levels declined by >50% following DEXA-BEAM and myeloablative therapy for 6 of 7 patients, with progression-free survival ranging from 4+ to 30+ months. All three evaluable patients, who were previously treated, also attained a major response in a study by Anagnostopoulos et al180 in which WM patients received various preparative regimens and showed event-free survivals of 26+, 31, and 108+ months. Tournilhac et al181 recently reported the outcome of 18 WM patients in France who received high-dose chemotherapy followed by autologous stem cell transplantation. All patients were previously treated with a median of three (range 1–5) prior regimens. Therapy was well tolerated with an improvement in response status observed for seven patients (six PR to CR; one SD to PR), while only one patient demonstrated progressive disease. The median event-free survival for all non-progressing patients was 12 months. Tournilhac et al181 have also reported the outcome of allogeneic transplantation in ten previously treated WM patients (ages 35–46) who received a median of three prior therapies, including three patients with progressive disease despite therapy. Two of three patients with progressive disease responded, and an improvement in response status was observed in 5 patients. The median event-free survival for non-progressing, evaluable patients was 31 months. Concerning in this series was the death of three patients owing to transplantation related toxicity. Anagnostopoulos et al182 have also reported on a retrospective review of WM patients who underwent either autologous or allogeneic transplantation, and whose outcomes were reported to the International Blood and Marrow Transplant Registry. Seventy-eight percent of patients in this cohort had 2 or more previous therapies, and 58% of them were resistant to their previous therapy. The relapse rate at 3 years was 29% in the allogeneic group, and 24% in the autologous group. Non-relapse mortality however was 40% in the allogeneic group, and 11% in the autologous group in this series.

Kyriakou et al183 recently provided an update of data from the European Bone Marrow Transplant (EBMT) registry on the outcome of WM patients who received either an autologous or allogeneic SCT. Among 202 WM patients receiving an autologous SCT, which included primarily relapsed or refractory patients, the 5 year progression free and overall survival rate was 61% and 33%, respectively. Chemosensitive disease at time of the autologous SCT was the most important prognostic factor for non-relapse mortality, response rate, progression free and overall survival. The EBMT experience with 106 allogeneic transplantation, which included 44 patients who received a conventional myeloablative allogeneic SCT and 62 patients who received a reduced intensity conditioning allogeneic SCT was also presented by Kyriakou et al183, which included predominately more advanced WM patients and was notable for 3 year non-relapse mortality rate of 33%. The 5 year progression free and overall survival rates in this series were 48% and 63%, respectively. Among the 106 patients who underwent an allogeneic SCT, 48 developed acute, and 16 and 11 patients developed limited and extensive chronic graft versus host disease, respectively. The potential role for reduced intensity conditioning (RIC) allogeneic SCT to induce responses, including complete responses, among patients with very advanced WM was reported by Maloney and Anderson184 who observed 6 complete, 1 near complete, and 4 partial responses among 12 evaluable patients. In consensus statements adopted at the 5th International Workshop, the use of autologous, as well as RIC allogeneic SCT were deemed appropriate modalities for the treatment of relapsed/refractory WM patients, though the risks and benefits of these modalities should be carefully weighed against other available treatment options.

 

RESPONSE CRITERIA IN WALDENSTROM’S MACROGLOBULINEMIA

Assessment of response to treatment WM has been widely heterogeneous. As a consequence studies using the same regimen have reported significantly different response rates. As part of the second and third International Workshops on WM, consensus panels developed guidelines for uniform response criteria in WM.185,186 The category of minor response was adopted at the Third International Workshop of WM, given that clinically meaningful responses were observed with newer biological agents and is based on >25 to < 50% decrease in serum IgM level, which is used as a surrogate marked of disease in WM. In distinction, the term major response is used to denote a response of > 50% in serum IgM levels, and includes partial and complete responses.186 Response categories and criteria for progressive disease in WM based on consensus recommendations are summarized in Table 4.  An important concern with the use of IgM as a surrogate marker of disease is that it can fluctuate, independent of tumor cell killing, particularly with newer biologically targeted agents such as rituximab and bortezomib.134-136,152,178 Rituximab induces a spike or flare in serum IgM levels which can occur when used as monotherapy and in combination with other agents including cyclophosphamide, nucleoside analogues, thalidomide and lenalidomide, and last for several weeks to months138,141,142,152,159,175,176,187, whereas bortezomib can suppress IgM levels independent of tumor cell killing in certain patients.159,188 Moreover, Owen et al189 showed that in patients treated with selective B-cell depleting agents such as rituximab and alemtuzumab, residual IgM producing plasma cells are spared and continue to persist, thus potentially skewing the relative response and assessment to treatment. Therefore, in circumstances where the serum IgM levels appear out of context with the clinical progress of the patient, a bone marrow biopsy should be considered inorder to clarify the patient’s underlying disease burden. A recent study by Ho et al37 suggests that’s soluble CD27 may serve as an alternative surrogate marker in WM, and may remain a faithful marker of disease in patients experiencing a rituximab related IgM flare, as well as plasmapheresis.190

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